Feasibility of clinical target volume reduction for glioblastoma treated with standard chemoradiation based on patterns of failure analysis.

PURPOSE: To analyze recurrence patterns in patients with glioblastoma (GBM) after standard chemoradiation according to different target volume delineation strategies. METHODS AND MATERIALS: Two hundred seven patients with GBM who recurred after standard chemoradiation were evaluated. According to ESTRO target volume delineation guideline, the CTV was generated by adding a 2-cm margin to the GTV, defined as the resection cavity plus residual tumor. Patterns of failure were analyzed using dose-volume histogram. Recurrent lesions were defined as in-field, marginal, or distant if > 80 %, 20-80 %, or < 20 % of the intersecting volume was included in the 95 % isodose line.For each patient, a theoretical plan consisting of reduced 1-cm GTV-to-CTV margin was created to compare patterns of failure and radiation doses to normal brain. RESULTS: Median overall survival and progression-free survival times were 15.3 months and 7.8 months, respectively, from the date of surgery. Recurrences were in-field in 180, marginal in 5, and distant in 22 patients. According to MGMT promoter methylation, distant recurrences occurred in 18.6 % of methylated and 6 % of unmethylated tumors (p = 0.0046). Following replanning with 1-cm reduced margin, dosimetric analysis showed similar patterns of failure. Recurrences were in-field, marginal, and distant in 177, 3, and 27 plans, respectively, although radiation doses to the healthy brain and hippocampi were significantly lower compared with standard target delineation (p = 0.0001). CONCLUSION: Current provide the rationale for evaluating GTV-to-CTV margin reduction in future clinical trials with the aim of limiting the cognitive sequelae of GBM irradiation while maintaining survival benefits of standard chemoradiation.

Single-isocenter multiple-target stereotactic radiosurgery for multiple brain metastases: dosimetric evaluation of two automated treatment planning systems.

PURPOSE: Automated treatment planning systems are available for linear accelerator (linac)-based single-isocenter multi-target (SIMT) stereotactic radiosurgery (SRS) of brain metastases. In this study, we compared plan quality between Brainlab Elements Multiple Brain Metastases (Elements MBM) software which utilizes dynamic conformal arc therapy (DCAT) and Varian HyperArc (HA) software using a volumetric modulated arc therapy (VMAT) technique. PATIENTS AND METHODS: Between July 2018 and April 2021, 36 consecutive patients ≥ 18 years old with 367 metastases who received SIMT SRS at UPMC Hillman Cancer San Pietro Hospital, Rome, were retrospectively evaluated. SRS plans were created using the commercial software Elements MBM SRS (Version 1.5 and 2.0). Median cumulative gross tumor volume (GTV) and planning tumor volume (PTV) were 1.33 cm3 and 3.42 cm3, respectively. All patients were replanned using HA automated software. Extracted dosimetric parameters included mean dose (Dmean) to the healthy brain, volumes of the healthy brain receiving more than 5, 8,10, and 12 Gy (V5Gy, V8Gy, V10Gy and V12Gy), and doses to hippocampi. RESULTS: Both techniques resulted in high-quality treatment plans, although Element MBM DCAT plans performed significantly better than HA VMAT plans, especially in cases of more than 10 lesions). Median V12Gy was 13.6 (range, 1.87-45.9) cm3 for DCAT plans and 18.5 (2.2-62,3) cm3 for VMAT plans (p < 0.0001), respectively. Similarly, V10Gy, V8Gy, V5Gy (p < 0.0001) and median dose to the normal brain (p = 0.0001) were favorable for DCAT plans. CONCLUSIONS: Both Elements MBM and HA systems were able to generate high-quality plans in patients with up to 25 brain metastases. DCAT plans performed better in terms of normal brain sparing, especially in patients with more than ten lesions and limited total tumor volume.

Neurological outcome and memory performance in patients with 10 or more brain metastases treated with frameless linear accelerator (LINAC)-based stereotactic radiosurgery.

PURPOSE: To assess the neurocognitive function and neurological toxicity of frameless linear accelerator (LINAC)-based stereotactic radiosurgery (SRS) in patients with 10 or more brain metastases (BM). PATIENTS AND METHODS: Forty consecutive adult patients who received SRS for ten or more 10 BM < 3 cm in maximum size were evaluated. All plans were generated using a single-isocenter multiple-target (SIMT) SRS technique with doses of 22 Gy for lesions < 2 cm and 16-18 Gy for those ≥ 2 cm in size. Survival analyses were estimated by Kaplan-Meier method from the date of SRS. Neurocognitive function using the Hopkins verbal learning test-revised (HVLT-R) and activity of daily living scale (ADLS) were collected prospectively at baseline and at 3,6 and 12-month follow-up. Toxicity was assessed by the National Cancer Institute Common Toxicity Criteria for Adverse Events (Version 5.0). RESULTS: With a median follow-up of 10.8 months, 1-year survival and local control rates were 65% and 86%, respectively. Grade 2 or 3 toxicity occurred in eleven patients, being associated with radiological changes suggestive of radiation necrosis in seven patients. Three months after SRS, the mean relative decline was 14.2% for HVLT-R delayed recall, 12.3% for HVLT-R recognition, and 9.8% for HVLT-R total recall. A significant deterioration of HVLT-R scores ranged from 5.5 to 18.7% of patients at different time points. ADLS scores declined over time, but changes were not significant. CONCLUSIONS: SRS is an effective and safe approach for patients with 10 or more BM able to maintain the pretreatment neurocognitive function in the majority of patients.

Stereotactic ablative radiation therapy as a potential curative treatment in duodenal adenocarcinoma: a case report.

PURPOSE: One of the rarest gastrointestinal neoplasm is small bowel cancer. Experience with its treatment modalities is limited. Stereotactic ablative radiation therapy (SABR) has improved, with image-guided radiation therapy becoming a curative option in many tumors. Especially when surgery cannot be performed due to comorbidities, SABR provides a good toxicity profile and an excellent tumor control rate owing to its specific schedule: high dose on a limited and well-defined area. METHODS: An 83-year-old man had arterial hypertension and congestive cardiomyopathy, with recent history of upper abdominal pain, weight loss over 10 kg, and progressive severe fatigue. The patient underwent endoscopy that showed a large mass partially obstructing the second part of the duodenum; a biopsy revealed a moderately differentiated adenocarcinoma. A staging CT scan confirmed localized disease. Due to the patient's age and comorbidities, a SABR was proposed as the preferred treatment. In order to localize the tumor during radiotherapy sessions, surgical clips were placed endoscopically next to the lesion as fiducial markers. The patient received 25 Gy in 5 fractions on alternate days. RESULTS: Resolution of duodenal obstruction and bleeding lasted for 14 months. The patient died of myocardial infarction. CONCLUSIONS: This case suggests that SABR could have a role in the palliative treatment of small bowel cancers, with good toxicity profile, particularly in patients for whom surgical treatment is not a viable option.

Temozolomide induced c-Myc-mediated apoptosis via Akt signalling in MGMT expressing glioblastoma cells.

PURPOSE: We investigated the molecular mechanisms underlying the cytotoxic effect of Temozolomide (TMZ) in both O(6)-methylguanine-DNA methyl transferase (MGMT) depleted as well as undepleted glioblastoma cell lines. Since TMZ is used in clinics in combination with radiotherapy, we also studied the effects of TMZ in combination with ionising radiation (IR). METHODS: Cell colony-forming ability was measured using a clonogenic assay. Cell cycle analysis and apoptosis were evaluated by Flow Cytometry (FCM). Proteins involved in cell cycle control were detected by Western blot and co-immunoprecipitation assays. RESULTS: Our data showed that TMZ, independent of MGMT expression, inhibited glioblastoma cell growth via an irreversible G(2) block in MGMT depleted cells or the induction of apoptosis in MGMT normal expressing cells. When TMZ was administered in combination with IR, apoptosis was greater than observed with either agent separately. This TMZ-induced apoptosis in the MGMT expressing cells occurred through Akt/Glycogen-Synthase-Kinase-3ß (GSK3ß) signalling and was mediated by Myelocytomatosis (c-Myc) oncoprotein. Indeed, TMZ phosphorylated/activated Akt led to phosphorylation/inactivation of GSK3ß which resulted in the stabilisation of c-Myc protein and subsequent modulation of the c-Myc target genes involved in the apoptotic processes. CONCLUSION: C-Myc expression could be considered a good indicator of TMZ effectiveness.

Mitotane sensitizes adrenocortical cancer cells to ionizing radiations by involvement of the cyclin B1/CDK complex in G2 arrest and mismatch repair enzymes modulation.

Mitotane inhibits steroid synthesis by an action on steroidogenic enzymes, as 11beta-hydroxylase and cholesterol side chain cleavage. It also has a cytotoxic effect on the adrenocortical cells and represents a primary drug used in the adrenocortical carcinoma (ACC). H295R and SW13 cell lines were treated with mitotane 10(-5) M and ionizing radiations (IR) in combination therapy, inducing an irreversible inhibition of cell growth in both adrenocortical cancer cells. As shown in a previous report, mitotane/IR combination treatment induced a cell accumulation in the G2 phase. Here, we report the radiosensitizing properties of mitotane in two different ACC cell lines. The drug reveals the effectiveness to enhance the cytotoxic effects of IR by attenuating DNA repair and interfering on the activation of mitosis promoting factor (MPF), mainly regulated by the degradation of cyclin B1 in the mitotic process. These events may explain the inappropriate activation of cdc2, implicated in G2/M phase arrest and probably induced by the mitotane and IR in the combined treatment. Indeed, treatment with purvalanol, a cdc2-inhibitor prevents cell cycle arrest, triggering the G2/M transition. The observation that mitotane and IR in combination treatment amplifies the activation level of cyclin B/cdc2 complexes contributing to cell cycle arrest, suggests that the MPF could function as a master signal for controlling the temporal order of different mitotic events. Moreover, we report that mitotane interferes in modulation of mismatch repair (MMR) enzymes, revealing radiosensitizing drug ability.

Fractionated ionizing radiation exposure induces apoptosis through caspase-3 activation and reactive oxygen species generation.

BACKGROUND: Radiation therapy (RT) is a well established therapeutic modality for the treatment of solid tumors. In particular, post-operative RT is considered the standard treatment adjuvant to surgery since its ability to prolong median survival of patients with malignant astrocytoma has been shown; nevertheless the ionizing radiation (IR) treatment fails in a considerable number of astrocytoma patients. MATERIALS AND METHODS: Using an ADF human astrocytoma cell line the molecular mechanisms involved in the DNA damage induced by fractionated irradiation (FIR) and single IR treatment have been investigated. RESULTS: FIR and single IR treatment inhibited the growth of the ADF human astrocytoma cell line. FACS analysis revealed that FIR treatment, but not single IR treatment, induced growth inhibition associated with the induction of apoptosis. Apoptosis was related to caspase-3 activation and reactive oxygen species (ROS) generation. ROS formation depends on the up-regulation of the cytochrome P450 enzyme gene. On the contrary, 12.5 Gy induced necrotic cell death up-regulating the HSPD1, HSPCB, HSPCA and HSPB1 genes. CONCLUSION: FIR treatment induced cell death through caspase-3 and ROS-mediated apoptosis.

Myc down-regulation sensitizes melanoma cells to radiotherapy by inhibiting MLH1 and MSH2 mismatch repair proteins.

PURPOSE: Melanoma patients have a very poor prognosis with a response rate of <1% due to advanced diagnosis. This type of tumor is particularly resistant to conventional chemotherapy and radiotherapy, and the surgery remains the principal treatment for patients with localized melanoma. For this reason, there is particular interest in the melanoma biological therapy. EXPERIMENTAL DESIGN: Using two p53 mutant melanoma models stably expressing an inducible c-myc antisense RNA, we have investigated whether Myc protein down-regulation could render melanoma cells more susceptible to radiotherapy, reestablishing apoptotic p53-independent pathway. In addition to address the role of p53 in the activation of apoptosis, we studied the effect of Myc down-regulation on radiotherapy sensitivity also in a p53 wild-type melanoma cell line. RESULTS: Myc down-regulation is able per se to induce apoptosis in a fraction of the cell population (approximately 40% at 72 hours) and in combination with gamma radiation efficiently enhances the death process. In fact, approximately 80% of apoptotic cells are evident in Myc down-regulated cells exposed to gamma radiation for 72 hours compared with approximately 13% observed after only gamma radiation treatment. Consistent with the enhanced apoptosis is the inhibition of the MLH1 and MSH2 mismatch repair proteins, which, preventing the correction of ionizing radiation mismatches occurring during DNA replication, renders the cells more prone to radiation-induced apoptosis. CONCLUSIONS: Data herein reported show that Myc down-regulation lowers the apoptotic threshold in melanoma cells by inhibiting MLH1 and MSH2 proteins, thus increasing cell sensitivity to gamma radiation in a p53-independent fashion. Our results indicate the basis for developing new antitumoral therapeutic strategy, improving the management of melanoma patients.